Rapid generation of anti-idiotypic antibodies

a technology of anti-idiotypic antibodies and anti-idiotypic antibodies, which is applied in the field of rapid generation of anti-idiotypic antibodies, can solve the problems of difficult and time-consuming anti-idiotypic antibody generation, prolonged immunizations, and difficulty in generating anti-idiotypic antibody serum titers in mice for monoclonal antibody generation, so as to reduce immune surveillance, shorten the half-life of a therapeutic drug, and reduce or eliminate side effects

Active Publication Date: 2018-12-11
BIOGEN MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]In one embodiment, the present invention provides a method of decreasing the half-life of a therapeutic antibody in a subject comprising administering an effective amount of an anti-idiotypic antibody of the invention to the subject, wherein the anti-idiotypic antibody specifically binds the therapeutic antibody. In one embodiment, the present invention provides a method of minimizing the adverse effects of a therapeutic antibody in a subject comprising administering an effective amount of an anti-idiotypic antibody of the invention to the subject, wherein the anti-idiotypic antibody specifically binds the therapeutic antibody. In one embodiment, the subject is human. In another embodiment, the therapeutic antibody is abciximab, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, certolizumab, daclizumab, eculizumab, efalizumab, gemtuzumab, ibritumomab, infliximab, natalizumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tositumomab, or trastuzumab. In a further embodiment, the therapeutic antibody is rituximab.

Problems solved by technology

Accurate quantification of circulating therapeutic antibody levels is an important and frequently challenging aspect of antibody drug development.
Since generating anti-idiotypic antibodies has been difficult and time consuming, these efforts were not focused on providing individualized therapies, but rather by generating cross-reactive anti-idiotypic antibodies that recognized shared idiotopes of the B-cell receptors on clonally distinct lymphomas from multiple patients.
The generation of anti-idiotype serum titers in mice for monoclonal antibody generation can be challenging and requires prolonged immunizations.

Method used

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  • Rapid generation of anti-idiotypic antibodies

Examples

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example 1

Experimental Procedures

[0075]Generation of Mouse Anti-Mouse CD20 18B12. Generation of the mouse anti-mCD20 hybridoma 18B12 and its isotype variants was as described in Patent Application US 2007 / 0136826 A1, incorporated herein by reference.

[0076]Mice. NOD (male and female), female SJL, male SWR, male NOR, male C.B-17, male C57BL / 6, and BALB / c mice (male and female) were purchased from the Jackson Laboratories (Bar Harbor, Me.) and housed in the animal facility at Biogen Idec. NOD, NOR, SJL, and C.B-17 mice express the Igh-1b allele of IgG2a (IgG2c); BALB / c mice express the Igh-1a allele (IgG2a); and SWR mice express the Igh-Ic gene. NOR mice are a recombinant congenic strain in which limited regions (˜15%) of the NOD genome have been replaced by genome from the C57BL / KsJ strain in order to map diabetes-related genes (Serreze et al., 1994). Mice were between 8-12 weeks old at the start of all studies. NOD mice were used for all anti-idiotypic antibody generation studies except as not...

example 2

Anti-mCD20 IgG2a Isotype Generates an Amplifiable Anti-Idiotypic Antibody Response in NOD Mice

[0083]To test whether the anti-idiotypic antibody response in NOD mice to anti-mCD20 18B12 IgG2a required the IgG2a Fc NOD mice were dosed with either anti-mCD20 18B12 IgG1a, IgG1b, IgG2b, IgG2c, IgG2a, or anti-mCD20 18B12 afucosyl IgG2a and the sera examined for antibody titers to the 18B 12 variable domains. Antibodies were administered in PBS without the adjuvant frequently used during anti-idiotype immunizations. Assessment of sera titers on day 10 post-dosing identified a strong titer of anti-idiotypic IgG antibodies generated to anti-mCD20 18B12 variable domains in mice dosed with 18B12 IgG2a or 18B12 afucosyl IgG2a, but not in those mice dosed with anti-mCD20 18B12 IgG1a, IgG1b, or IgG2b (FIG. 2A). A weak anti-idiotypic IgG response to anti-mCD20 18B12 variable domains was found in mice dosed with anti-mCD20 18B12 IgG2c.

[0084]Additionally, we investigated whether the anti-idiotypic a...

example 3

Enhanced Immunogenicity of Antigens Co-Administered with Anti-mCD20 IgG2a in NOD Mice is Restricted to Variable Domains of Mouse IgG2a Antibodies

[0086]To test whether the enhanced idiotype immunogenicity found in NOD mice after anti-mCD20 IgG2a treatment could be expanded to antigens that were not intact antibodies, mice were immunized with trinitrophenyl (TNP)-KLH (keyhole limpet hemocyanin) and TNP-Ficoll (T-dependent and T-independent antigens, respectively) with or without anti-mCD20 IgG2a co-administration. Additionally, a fusion protein comprised of the extracellular domain of human BDCA2 linked to the mIgG2a Fc and a rat anti-mouse CD103 antibody engineered as a chimeric mouse IgG2a antibody were selected for co-immunization with anti-mCD20 IgG2a. TNP conjugates and human BDCA2, as expected, were immunogenic in the absence of anti-mCD20 IgG2a treatment (FIG. 4). Co-administration of anti-mCD20 IgG2a did not significantly increase their immunogenicity (FIG. 4) although there w...

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Abstract

The present disclosure relates to in vivo methods for producing anti-idiotypic antibodies. In some aspects, anti-idiotypic antibodies are generated by co-administering to a mouse a first antibody having a murine IgG2a isotype and a second antibody that targets mouse B cells and has a murine IgG2a isotype. In some embodiments, the mouse expresses the Igh-1b allele of IgG2a, and the second antibody binds a mouse B cell surface marker selected from the group consisting of CD19, CD20, CD21, CD22, CD40, CD45, IgM, and IgD.

Description

BACKGROUND OF THE INVENTION[0001]Field of the Invention[0002]The present invention provides methods for generating anti-idiotypic antibodies and compositions comprising the antibodies.[0003]Background Art[0004]Anti-idiotypic antibodies are defined as antibodies that target specific epitopes, called isotopes, on another antibody that are unique for that target antibody. The collection of isotopes for a given antibody defines its idiotype, and is generally found in the complementarity determining regions (CDRs) of the targeted antibody. Polyclonal anti-idiotypic antibodies have been used experimentally since the 1950's, but it was not until the mid-1970's that a modern theory was proposed for how self-generated anti-idiotypic antibodies might help control the immune system by regulating antibody production (Jerne, 1974). The discovery of a method for producing monoclonal antibodies a year later (Köhler and Milstein, 1975) opened the door for the creation and isolation of monoclonal an...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07K16/42C07K16/28
CPCC07K16/4258C07K16/4208C07K16/2887C07K2317/52A61P21/04A61P37/04A61P37/06A61P43/00
Inventor DUNN, ROBERT J.KEHRY, MARILYN R.
Owner BIOGEN MA INC
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